Personal View

Precision oncology: origins, optimism, and potential

Vinay Prasad, Tito Fojo, Michael Brada

Imatinib, the first and arguably the best targeted therapy, became the springboard for developing drugs aimed at Lancet Oncol 2016; 17: e81–86
molecular targets deemed crucial to tumours. As this development unfolded, a revolution in the speed and cost of Division of Hematology
genetic sequencing occurred. The result—an armamentarium of drugs and an array of molecular targets—set the Oncology, Knight Cancer
Institute, Department of Public
stage for precision oncology, a hypothesis that cancer treatment could be markedly improved if therapies were guided
Health and Preventive
by a tumour’s genomic alterations. Drawing lessons from the biological basis of cancer and recent empirical Medicine, and Center for
investigations, we take a more measured view of precision oncology’s promise. Ultimately, the promise is not our Health Care Ethics, Oregon
concern, but the threshold at which we declare success. We review reports of precision oncology alongside those of Health and Science University,
Portland, OR, USA
precision diagnostics and novel radiotherapy approaches. Although confirmatory evidence is scarce, these
(V Prasad MPH); Columbia
interventions have been widely endorsed. We conclude that the current path will probably not be successful or, at a University and James J Peters
minimum, will have to undergo substantive adjustments before it can be successful. For the sake of patients with Veterans Affairs Medical
cancer, we hope one form of precision oncology will deliver on its promise. However, until confirmatory studies are Center, New York, NY, USA
(Prof T Fojo PhD); and
completed, precision oncology remains unproven, and as such, a hypothesis in need of rigorous testing. Department of Molecular and
Clinical Cancer Medicine &
Introduction Although an attractive concept—made all the more Department of Radiation
The emergence of imatinib as a therapy for patients attractive by the lay press and its fascination with Oncology University of
Liverpool Clatterbridge Cancer
with chronic myeloid leukaemia was met with great precision medicine narratives—the challenges of Centre NHS Foundation Trust
enthusiasm. Seen as a validation of the promise of precision oncology remain daunting. Yet political, Bebington, UK
molecularly targeted therapies,1 doctors, researchers, societal, and, most importantly, economic pressures (Prof M Brada DSc)
and thought-leaders envisioned the identification of have taken over part of the narrative. In the USA, an Correspondence to:
Bcr-abl equivalents in all cancers and the development endorsement by US President Barack Obama in the Prof Tito Fojo, Columbia
University and James J Peters
of targeted therapies similar to imatinib. When imatinib form of a US$215 million Precision Medicine Initiative Veterans Affairs Medical Center,
was subsequently shown to have efficacy in gastro- set the tone and a high bar for success.11 However, New York, NY 10032, USA
intestinal stromal tumours2—a previously intractable societal and economic pressures have been most [email protected]
cancer—many people thought it was only a matter of influential. With countless articles in the lay press
time before even the most difficult cancer was tamed. In reporting miraculous narratives of patients treated with
the enthusiasm that followed, concerns that more lethal a targeted therapy, an increasing number of patients
cancers might have more complex molecular alterations3 request such tests or present to their doctors with results
than chronic myeloid leukaemia and gastrointestinal in hand asking that their cancer be tamed.12 This
stromal tumours were set aside, and the targeted response is not surprising. Who would not be enticed by
therapy revolution gained steam propelled by many the idea that their tumour is unique and can be precisely
pharmaceutical partners.4 targeted by one of the many targeted drugs reportedly
At the same time, the genomic revolution was also available? Not surprisingly, countless enterprises have
underway.5 With the elucidation of the human genome seen the potential windfall in revenue from this demand
sequence, the identification of molecular alterations that and have risen to provide these services. Even more
drove each cancer seemed certain, and sequencing was importantly, institution after institution has fallen prey
expected to occur with increasing speed and at remarkably to this phenomenon, in recognition that if they do not
low prices. However, in more complex cancers, there were offer precision oncology, their business will be adversely
more molecular alterations than first imagined.6 The affected as patients and pharmaceutical companies flock
relentless development of targeted therapies in the decade to competing institutions.
and half that followed—none nearly as specific and Is the hope realistic? Perhaps not. Accumulated evidence
valuable as imatinib and trastuzumab—meant that, for an indicates that tumours harbour a large number of
increasing number of molecular alterations, drugs that molecular alterations, and for one of the many molecular
could possibly target the aberrant functions such alterations to be targeted to achieve a clinically significant,
molecular alterations engendered were available. This sustained effect might not be realistic for most tumours.
development also led to the term actionable mutation Why would a drug, such as a BRAF inhibitor, which brings
being coined, and to countless papers that nominated only a modest benefit in a disease such as melanoma
candidate target genes,7,8 which, in turn, led to the concept (for which BRAF is important), achieve so much more in a
of personalised medicine. When old-school doctors tumour in which it has occurred randomly.
complained that their care had always been Despite these challenges, several trials and initiatives
personalised—a belief ratified by the then NCI Director, for precision medicine were launched. A few studies
Harold Varmus, who in an interview noted that his have been published, and a few more are ongoing.
father’s care of patients had been tailored and personal—a Preliminary results can best be characterised as very
shift to precision medicine as the preferred term ensued.9,10 modest and generated in what are arguably ideal settings

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and patients, and one can certainly imagine less benefit people believe the number of previous lines of therapy
in a community practice, among older patients with tells us how sick patients are—with the implication that
comorbidities, and in developing countries. the greater number of previous lines of therapy, the worse
While the jury is still out on whether the promise of the patient cohort—we would argue that it tells something
precision oncology can be delivered, we do not believe that equally, if not more, important about the biology of their
the lofty expectations described at the turn of this century cancer. Patients with relatively indolent tumours live long
will be met. In its simplest iteration, the modern enough to see more treatment, whereas those patients
expectation is that all patients with cancer would undergo with rapidly progressing illnesses do not. This is an
germline and tumour sequencing to identify a unique important variable if one is to assign value to the duration
mutational profile that will guide a highly effective therapy of a response, since the more indolent the growth of the
with few side effects. The more realistic outcome is that, tumour, the longer the duration of a response could be in
in some cases, the course of specific illnesses with clear, comparison with patients who have aggressive tumours.
identifiable molecular participants (like chronic myeloid Given this notion, the duration of response to a previous
leukaemia) might be dramatically altered. In more cases, line of therapy could be an important statistic but was
modest prolongations of life—measured in a few only reported in 29 (52%) of 32 cases of super responders.
months—might be achieved, but these cases might also In another study,15 in which investigators used each
be rare. In most cases, oncologists might simply end up patient as his or her own control, molecularly guided
delivering therapies that are more toxic than conventional therapy was found to improve progression-free survival
chemotherapy regimens, with marginal to no gain in by an arbitrary and modest 30% relative to previous
survival. progression-free survival in only 18 (27%) of 66 patients.
Much like the practitioners who are now advocating Results of a study16 from the MD Anderson Cancer
protons as the answer to all our radiotherapy needs, Center, although encumbered by its retrospective
oncologists long frustrated with marginal outcomes are nature, showed that patients who entered phase 1
pinning hopes on precision oncology. However, those testing and received therapy matched against their
oncologists who practice precision oncology are two steps molecular alterations had better responses, time to
ahead of the data—and the history of medicine has treatment failure, and survival than patients who
taught us that is an uncertain place to stand. received unmatched therapy.
The validity of all therapeutic hypotheses are best
In need of empirical verification ascertained in robust, randomised studies, and these
Precision oncology, despite its laudation and appeal to studies are now ongoing or, in the case of the French
both doctors and patients alike, remains a hypothesis in SHIVA trial, already reported.17 The SHIVA trial was a
need of empirical study. As is often the case in medicine, proof-of-concept, open-label trial in which patients with
initial reports were encouraging, and consisted largely of solid tumours who had tried all regimens known to
case reports of exceptional and super responders to confer a survival benefit (including molecularly targeted
cancer therapy and of small groups of patients who were agents) were randomly assigned to pathway-directed
not enrolled in randomised trials.13 Systematic reviews therapy (precision oncology) or clinician’s choice
have clarified these findings: 32 cases of exceptional and (control). Randomisation was stratified by three pathways:
super responders to cancer drugs can be found in the a hormone receptor pathway; a P13K/AKT/mTOR
biomedical literature.14 The use of a targeted therapy was pathway; and a RAF/MEK pathway. The molecularly
common among these super responders, occurring in targeted agents used were erlotinib, sorafenib, imatinib,
26 (81%) of 32 cases, and inhibitors of the mTOR pathway dasatinib, vemurafenib, everolimus, abiraterone, letrozole,
were particularly prominent, accounting for 16 (50%) and tamoxifen. The primary endpoint was progression-
published reports.14 Some responses appeared exceptional, free survival, and bidirectional crossover was used.
with a reported median duration of response of 741 patients were screened, and 99 patients were
17∙5 months. Yet, several problematic omissions of randomly assigned to the precision oncology group and
reporting were noted. Specifically, only 12 (38%) cases 96 patients to usual care. With a median follow up of
reported the number of patients who had been treated 11∙3 months in both groups, median progression-free
similarly to find the super response. This statistic has survival did not improve for patients in the precision
importance and is especially relevant to community oncology group (2∙3 months [95% CI 1·7–3·8] in the
oncologists who need to consider whether the potential experimental group vs 2∙0 months [1·8–2·1] in the
benefits to responders are offset by toxic effects to the control group; p=0∙41). Patients in the experimental
larger number of non-responders. When reported, this group did not outperform those in the control group in
number ranged from three (100%) in three patients to any of the three prespecified pathway strata. Not only did
one (0∙6%) in 151 patients. 26 (81%) of 32 cases reported precision oncology have little efficacy, but it appeared to
the number of previous lines of therapy. When previous cause more toxic effects than chemotherapy did.
lines of therapy were reported, two or more previous lines Treatment interruptions or dose delays—a marker
of therapy were given in 12 (46%) cases. Whereas many of tolerability18,19—were also more common in the

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experimental group (30%) than in the control group groups recruited just 29 patients and yielded just
(18%), as were grade 3–4 toxic effects (43% in the two partial responses (7%). The responses seen in these
experimental group vs 35% in the control group).17 true investigational groups in a well designed basket trial
As is a common theme in the history of medicine,20,21 are barely higher than that of an unselected sample of
the results of the randomised SHIVA trial, although phase 1 trials (4%).24
perhaps somewhat underpowered, contradict the more
optimistic estimates of precision medicine in early Precision diagnostics
reports. In fairness, however, the disappointing results of Some challenges of precision medicine extend beyond
the SHIVA trial do not mean precision oncology will fail, treatment and to precision diagnostics. Although several
but simply that the strategy, as tested, does not work. molecular techniques are used to aid traditional
However, because the tested strategy is consistent with diagnostics, one clear example of the early adoption of an
the growing off-protocol use of these drugs, results of the unproven method is the growing use of gene expression
SHIVA trial should serve as a powerful deterrent against profiling in the diagnosis of carcinoma of unknown
the off-protocol use of unapproved targeted drugs, a primary (CUP).25 The diagnosis of CUP carries a sobering
conclusion the trial investigators share.17 prognosis, with results of recent phase 2 trials showing
Additional reason to be cautious about precision median overall survival of around 12 months.26 Historically,
oncology comes from a recent report of a so-called the approach to CUP was to combine a patient’s medical
basket study22 that enrolled patients with diverse tumour history and physical examination, radiographic findings,
types containing BRAF V600 mutations. Patients were and pathological results (including immunohisto-
treated across prespecified cancer cohorts, including chemistry) to make a best approximation of the tissue of
non-small-cell lung cancer, colon cancer, multiple origin, and to use an empiric chemotherapy regimen. Yet
myeloma, cholangiocarcinoma, Erdheim-Chester or in recent years, one more diagnostic method is being
Langerhans’ cell histiocytosis, anaplastic thyroid cancer, applied to these cases to better characterise the tissue
and other cancers. Although objective responses were of origin—gene expression profiling. Like precision
reported in eight (40%) of 20 patients with non-small-cell oncology, gene expression profiling remains controversial
lung cancer, six (33%) of 18 patients with Erdheim-Chester and needs robust validation.27 Simply put, the controversy
or Langerhans’ cell histiocytosis, and two (29%) of is that characterisation of the tissue of origin might lead
seven patients with anaplastic thyroid cancer, responses to more specific tissue diagnoses, which could in turn
were recorded in only one (3%) of 37 patients with colon change some empiric chemotherapy regimens, although
cancer and one (13%) of eight patients with cholangio- the extent to which such substitutions are made
carcinoma. Grade 3–4 adverse events were seen in remains unreported. More importantly, whether these
69 (73%) of 95 patients. The most common adverse events substitutions will improve survival is unclear, and survival
were arthralgia (38 [40%] patients), diminished appetite is the bar against which the use of gene expression
(28 [30%] patients), and nausea (27 [28%] patients). profiling must be judged. Whether routine testing of the
Although the data for non-small-cell lung cancer must be tissue of origin can improve survival in patients with
validated, they represent only a very small fraction of all CUP is being investigated in an ongoing randomised trial
patients, and in a rare disease such as Erdheim-Chester (NCT01540058), but before this trial yields definitive
or Langerhans’ cell histiocytosis these initial findings results, the use of gene expression profiling continues
should be pursued. Most importantly, the results of off-protocol and is covered by many insurers. It must be
Hyman and colleagues’ study22 show that even an agent remembered that many plausible improvements in the
with high affinity for its target that is used in a setting of diagnosis or monitoring of other cancers, including the
a known susceptible molecular alteration might not use of immunohistochemistry to detect microscopic
work similarly across tumour types, highlighting the metastasis in sentinel lymph nodes,28 the monitoring of
importance of the disease context in which the molecular CA-125 after the initial treatment of ovarian cancer,29 and
alteration occurs. the use of surveillance imaging among patients with
Finally, in another basket trial of patients with advanced aggressive lymphoma who achieved complete response
non-small-cell lung cancer, Lopez-Chavez and colleagues23 with induction treatment,30 have not improved outcomes.
confirmed that anti-EGFR therapy and anti-ALK therapy The harms of early and untested use of precision
offer benefit to patients who have activating molecular diagnostics are tied to the uncertainty of the benefits.
alterations in EGFR and ALK, respectively. Unfortunately, In the case of testing tissue of origin, if routine use fails to
the investigators were unable to conclude much else, improve outcomes, the harms are fortunately limited
noting that “this basket trial design was not feasible for to financial waste. However, routine testing with gene
many of the arms”. No verdict was rendered with respect expression profiling could actually lead to inferior
to selumetinib for RAS or BRAF mutations, MK2206 for outcomes as changes in treatment are shifted from
PTEN/Akt1 or PIK3CA mutations, lapatinib for ERBB2 broad chemotherapy doublets with measurable activity to
mutation or amplification, and sunitinib for KIT or tailored therapies that have limited activity in these poorly
PDGFR mutation or amplification. Collectively, these trial differentiated cancers. In such cases, the harms are more

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concerning. The use of therapies directed by molecular The growth in the number of proton facilities is an
alterations carries a similar risk of either failing to confer example of a technology of which objective and rational
benefit and adding toxic effects, or doing so while discussion has become difficult. The rationale for
delaying the use of therapy with measurable and proven protons with more localised deposition of energy is
benefit, resulting in net harm. Finally, the untested use of undeniable, although the complexity of the technology
precision diagnostics to guide the timing of treatment and many of the uncertainties in the delivery of protons
might lead to more anti-cancer drug administration with are, in the wave of enthusiasm, not frequently voiced.
its attendant harms, without clinical benefit, akin to the The proponents’ view is that the favourable physical
situation with CA-125-guided ovarian cancer therapy.29 properties of protons are sufficient proof that they
offer superior treatment that will undoubtedly result
Precision radiotherapy in improved clinical outcomes. The public, fuelled
Radiotherapy has been at the forefront of technological by media reports about children going abroad for
advances in medicine, moving from low-energy X-rays life-saving proton therapy, believes that protons are a
and cobalt irradiation to the highly sophisticated use of miraculous new treatment.31 Proton providers tacitly, as
high-energy photons delivered by linear accelerators. well as more overtly, support this view. The apparently
Photon technology offers localised irradiation with great opposing academic argument demands evidence of
accuracy. The substantial leaps seen at the time of the clinical benefit for any of the tumour sites for which
initial introduction and maturation of this technology protons are offered.32
were followed by innovations that resulted predominantly Novel radiotherapy technology, including proton
in marginal gains. The introduction of protons and other therapy, comes with a hefty price tag and consequent
heavy charged particles, which offer the prospect of more commercial pressure. Initial assessment of the technology
localised delivery of ionising radiation, is considered a is in the hands of users with an interest in its success, and
step change in technology beyond the apparent plateau in this assessment can probably not be considered unbiased.
the evolution of photon-based external beam radiotherapy. Clinical assessment is almost invariably in the form of
The introduction of new technology necessitates phase 2 studies of selected cohorts, which would not pass
considerable investment in technical development with the rigour required for the registration of new drugs and
input from physics and engineering, not dissimilar to have led to missteps in cancer treatment.33
the demands in cancer drug development. Enthusiasm is Consider, for example, patients with skull-base
needed on the part of industry as well as technical and chordoma—a tumour that grows close to a critical neural
clinical research teams. Unlike the tightly regulated structure, with historically poor outcomes—who were
introduction of new medicinal products, the introduction treated in the early days of proton therapy. Initial results
of device and radiation technology has the lightest of suggested improved tumour control compared with
regulatory hurdles to overcome, and often does not historical controls.34 The subsequent drive to establish
mandate evidence of clinical benefit beyond that seen protons as the appropriate treatment in this niche
with previous technology. indication ignored improvements in surgery and
Growth of innovative technologies is generally high-precision photon radiotherapy that showed markedly
perceived to be of unbounded progress driven by many improved outcomes.35–37 Factors, such as the tumour size
technical improvements. Yet, in the absence of high- and the extent of surgery, were not acknowledged as
level evidence of benefit and limited information about perhaps the most important determinants of the
risk, such technologies are largely unproven. A prudent improvement. These shortcomings were coupled with
view is thus in line with our discussion of drugs: more poor quality reporting of incomplete cohorts with results
rigorous testing is needed to ensure true clinical benefit of questionable validity.38 Despite the absence of clear
before widespread introduction. Enthusiasts consider evidence that proton therapy is better than conventional
the theoretical benefit of innovation to be of value in treatment, the initial proposition remains unquestioned,
itself. The perception is that barriers to early and skull-base chordoma has become accepted as one of
introduction, including insistence on clinical evidence, the principal indications for proton therapy.
would deny patients access to new, effective treatments Without evidence of benefit of a new technology,
and suppress innovation and academic and entre- health-care providers and manufacturers, having made
preneurial spirit. Into this arena enter commercial substantial investments, resort to other strategies to
interests, health economics, and politics. To deny convince the public and funders to adopt new technology.
patients access to what the media often describe as One example is the creation of novel indications, marketed
novel, life-saving treatments (which, in terms of through press releases and direct political lobbying.12
technology, do not exist) is feared by governments as Although pressure from industry is a recognised
political suicide, and this reluctance is widely exploited mechanism to influence decisions makers, particularly on
by vested interests. Yet, not everything new in medicine the cost-effectiveness of new drugs, the influence of
is real innovation; instead, many advances turn out not industry on users in relation to new technologies slips
to work as intended and constitute pseudo-innovation. under the radar. The adoption of these technologies is

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often affected by the quantity of publications, irrespective

of their quality, and simply by the increased use of the Search strategy and selection criteria
technology despite the absence of high-level evidence. We searched MEDLINE for clinical trials published between
Dec 10, 2010, and Dec 10, 2015, using the term “precision
What can be done? oncology”. 128 reports in English were identified. We also
Much can be done before definitive evidence to support any selected additional material we were aware of, and all authors
precision approach to cancer is found. For precision drug agreed on the final selection of references. Trials that used the
use and precision diagnostics, properly conducted term “precision oncology” but essentially described
randomised clinical trials should be insisted on as essential conventional approaches to drug development and medicine,
evidence. While trial results mature, several goals must be and studies that reported solely pharmacological endpoints
met. First, assays to detect molecular alterations and rather than clinical endpoints were excluded.
identify gene expression profiles that can determine the
tissue of origin with improved precision must be validated
and shown to be reproducible. Second, these technologies melanoma are examples22,40), but one should not assume
must be able to reclassify cases such that the result becomes that the context or mutational background will be
the most important property of the tumour or, in the case equivalent or even similar everywhere in the world. Just as
of gene expression arrays, successfully reclassifies tumours the aetiology of cancer can vary worldwide, so too could the
that were indeterminate or misclassified using traditional mutational profile.41
approaches. Third, the results should lead to different The challenges in so many areas of the world to deliver
treatment recommendations. Finally, the application of even basic oncology cannot be ignored; these are
new technologies and new treatments should improve challenges that make precision oncology and radiotherapy
clinical outcomes where the comparator is a standard seem far off or even impossible. Recognition of this makes
treatment not guided by the new diagnostic.27 us uncomfortably aware that we are discussing a strategy
As for precision radiotherapy, the current system must that, for the foreseeable future, could only be an option for
be rectified to ensure the adoption of technology with real a small percentage of patients with cancer living in the
benefit, without stifling the quest for innovation. wealthiest nations. The acquisition of robust evidence is,
Unproven, costly, and potentially harmful treatments must therefore, especially important, indeed mandatory, if these
be rejected. The time has come for regulators, nation by technologies are to be deployed in areas of the world with
nation, to create a structure that is equivalent to that used fewer resources. For example, to obtain a sequence for all
for drug licensing and assessment of cost-effectiveness patients’ tumours and then administer what might be
by NICE in the UK, with the specific focus on novel prohibitively expensive therapies, is a thought that casts
technologies. An agreement between all stakeholders on some doubts on the idea that precision oncology will be
novel methods of assessment, ideally carried out transformative in most of the world any time soon.
independently, will be necessary but is a tall order when all Although admittedly a negative sentiment, the emerging
the cards are in the hands of the manufacturers and users data leads to a realisation that an inability to provide
and when barriers to confirmatory trials differ depending precision oncology more widely will not greatly affect
on whether the modality tested is radiation, drugs, or outcomes, and its limited deployment is thus not as
biological diagnostics. Improvements in radiotherapy concerning.
might constitute innovation; alternatively, the improve- For the sake of patients with cancer, we hope that
ments might merely offer false promise and be revealed as precision oncology, as currently envisioned or being
pseudo-innovation. Carefully designed, randomised practiced, will emerge as a viable option in years to
studies powered for important patient-centred endpoints come. However, emerging data is pointing to a need for
are the only way to find out whether a new technology will a major refinement in the theory and practice
have a real clinical benefit. Potential risks associated with underpinning the precision oncology framework. We do
precision radiotherapy, such as eventually missing (part of) not believe the current framework is sufficiently sound,
the target, is an aspect often overlooked when more and indeed we would argue it is too simplistic for
advanced radiation methods are assessed. complex cancers with innumerable molecular and
epigenetic alterations that have yet to be systematically
Conclusion defined, and will make a difficult problem even more
Whether an initiative such as precision oncology or complex and challenging. Similarly, for the same sake of
precision radiotherapy will ever be possible on a global patients with cancer, efforts in precision oncology should
scale is, of course, uncertain. The applicability of results be held to the bar of traditional oncology research and
from clinical trials to the general population has emerged practice, and meaningful improvements in clinical
as an important issue,39 especially for the precision outcomes ought to be tested in rigorous randomised
oncology hypothesis. The mutational landscape should not trials. If our assessment of the shortcomings of the
be assumed to be similar in all parts of the world. Context precision oncology framework is correct, then it is time
is clearly important (BRAF in colorectal cancer versus to redouble efforts and resources to seek better therapies.

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Contributors 21 Prasad V, Gall V, Cifu A. The frequency of medical reversal.

VP drafted the sections about precision oncology as a hypothesis in need Arch Intern Med 2011; 171: 1675–76.
of empirical verification and precision diagnostics. TF drafted the 22 Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple
introduction and the conclusion. MB drafted the section about the role of nonmelanoma cancers with BRAF V600 mutations. New Engl J Med
precision radiotherapy. VP and TF drafted the abstract. All three authors 2015; 373: 726–36.
drafted the section about what should be done. All authors revised the 23 Lopez-Chavez A, Thomas A, Rajan A, et al. Molecular profiling and
manuscript for important intellectual content, made comments on each targeted therapy for advanced thoracic malignancies:
other’s sections, and changed wording. All authors are guarantors. a biomarker-derived, multiarm, multihistology phase II basket trial.
J Clin Oncol 2015; 33: 1000–07.
Declaration of interests 24 Horstmann E, McCabe MS, Grochow L, et al. Risks and benefits of
We declare no competing interests. phase 1 oncology trials, 1991 through 2002. New Engl J Med 2005;
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